Mitochondrial Energy-Deficient Endophenotype in Autism

Abstract

Abstract:While evidence points to a multigenic etiology of most autism, the pathophysiology of the disorder has yet to be defined and the underlying genes and biochemical pathways they subserve remain unknown. Autism is considered to be influenced by a combination of various genetic, environmental and immunological factors; more recently, evidence has suggested that increased vulnerability to oxidative stress may be involved in the etiology of this multifactorial disorder. Furthermore, recent studies have pointed to a subset of autism associated with the biochemical endophenotype of mitochondrial energy deficiency, identified as a subtle impairment in fat and carbohydrate oxidation. This phenotype is similar, but more subtle than those seen in classic mitochondrial defects. In some cases the beginnings of the genetic underpinnings of these mitochondrial defects are emerging, such as mild mitochondrial dysfunction and secondary carnitine deficiency observed in the subset of autistic patients with an inverted duplication of chromosome 15q11-q13. In addition, rare cases of familial autism associated with sudden infant death syndrome (SIDS) or associated with abnormalities in cellular calcium homeostasis, such as malignant hyperthermia or cardiac arrhythmia, are beginning to emerge. Such special cases suggest that the pathophysiology of autism may comprise pathways that are directly or indirectly involved in mitochondrial energy production and to further probe this connection three new avenues seem worthy of exploration: 1) metabolomic clinical studies provoking controlled aerobic exercise stress to expand the biochemical phenotype, 2) high-throughput expression arrays to directly survey activity of the genes underlying these biochemical pathways and 3) model systems, either based upon neuronal stem cells or model genetic organisms, to discover novel genetic and environmental inputs into these pathways.

A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism

“…There are extensive reports of mitochondrial abnormalities in autism, as reviewed recently (25), and some of the mitochondrial dysfunction could be secondary to carnitine deficiency. There are reports of low plasma carnitine in autism (26)(27)(28)(29), but these reports have not prompted intensive investigations into a possible role of carnitine deficiency in autism and further studies are needed.…”

“…Features of autism generally are not reported in children with systemic carnitine deficiency, although cases of autism with carnitine deficiency have been reported (26). Given the neurological basis of autism and the prominent expression of TMLHE in hippocampal neurons and Purkinje cells, one possibility would be that symptoms of autism might be secondary to carnitine deficiency in the brain.…”

Interplay between pro-inflammatory cytokines and brain oxidative stress biomarkers: Evidence of parallels between butyl paraben intoxication and the valproic acid brain physiopathology in autism rat model

“…There is also ample evidence on the role of glutathione in both innate and adaptive immune functions, as well as an anti-inflammatory role [8,10,11]. Recently, evidence has suggested that increased exposure to oxidative stress, together with mitochondrial dysfunction [12,13] may contribute to the aetiology of multifactorial autism disorder, inflammation, and immune abnormalities [13]. Additionally, overactivation and inflammation of autism can result in an overproduction of NO.…”

A mitochondrial bioenergetic etiology of disease

“…Yet the genetics and pathophysiology of ASDs are fully consistent with the expectations for mild mitochondrial dysfunction. Like LHON (6), in ASDs, males are four times more likely than females to be affected (63,64). Mitochondrial metabolic defects have been repeatedly reported in ASD patients, and mtDNA mutations have been found in several ASD pedigrees (63,(65)(66)(67).…”